Current manufacturing technologies for cell removal from production-scale bioreactors use one of two options: disc stack centrifugation followed by depth filtration, or direct depth filtration (typically used for bioreactor volumes up to 2kL scale with lower cell densities).
Depth filtration approaches have a large footprint, a cumbersome installation process and reach their operational limits with final cell densities of around 50 million cells/mL. Existing technologies will be increasingly challenged due to the further intensification of processes, e.g. by perfusion (concentrated fed-batch systems with cell retention), which will need solutions that can operate with feedstream cell densities over 150 million cells/mL.
This is why BioPhorum has written the Harvest clarification URS. Version 2.0. This outlines biopharmaceutical manufacturers’ requirements for an improved harvest clarification solution that will operate with feedstream cell densities up to 150 million cells/mL in a single-use production scenario.
Finding ultra-high cell density solutions
“Cell removal and clarification is always neglected between upstream and downstream development,” said Hiren Ardeshna, Sr. Scientific Investigator at GlaxoSmithKline. “The recently published Harvest and Clarification URS will enable vendors and development teams to effectively test their technology to handle upstream cell density increases, while enabling intensified downstream processes that meet industry expectations for quality and yield.”
The URS contains requirement details covering functional requirements (e.g. operating temperature and temperature change), qualification requirements (e.g. microbial control), quality requirements (e.g. biocompatibility) and supply chain requirements (e.g. lead times).
To facilitate the development of new technologies, those for the clarification of high cell density feedstreams may be evaluated according to the testing parameters described in the URS’s addendum.
The new URS will bring consistency to the testing performed by vendors and help biomanufacturers to make better decisions about which solution technology they would like to use or investigate further. Without this consistency, there is variability in how vendors can demonstrate what their equipment and solutions can do, which prevents biomanufacturers from properly comparing systems.
The paper supports the original Harvest clarification URS that was written for a harvest clarification solution that will handle ultra-high-density mammalian cell cultures.
Both URSs have been driven by the process technologies chapter of the BioPhorum Biomanufacturing Technology Roadmap. This identified the need for robust harvesting systems that enable cost-effective upstream processing options, e.g. handling high-density suspensions, better/faster equipment cleanability and turnaround.
Thanks for posting the updated version of your URS for Harvest Clarification.
Sudhin Biopharma Company has been developing its single use disposable BioSettlers for this exact application over the past two years. After demonstrating our first prototype device (3.8 liters) to clarify 15 liter cell culture broth at two different big biopharma companies (the later one very successfully, after figuring out why it did not do so well at its first trial), we have now further optimized the design of our BioSettler for higher product recovery (>95%).
We have now fabricated our BioSettler device at smaller sizes (500 ml, 1000ml) for testing at other companies to harvest the clarified supernatant from 2 -5 liter fed-batch bioreactor cell culture broth.
In response to an enquiry from another big biopharma company, who have purchased one of these smaller devices for their own internal testing, we are now fabricating our device for increasing larger sizes, 20 liters and 50 liters, which are suitable for clarifying the cell culture broth from 100 liter and 250 liter fed-batch bioreactors. Our optimized biosettler can be scaled up (after your smaller scale trials) to clarify cell culture broth from 200 liter – 5000 liter bioreactors.
Dhinakar Kompala, Founder & CEO, Sudhin Biopharma Co., email@example.com